OBJECTIVES: To estimate direct medical costs of Tuberous Sclerosis Complex with neurological and developmental manifestations under the Brazilian public health care system perspective (SUS). METHODS: A retrospective database analysis was developed from ICD-10 search from January/2008 (revision of table of procedures by SUS Information Technology Department/DATASUS) to February/2011. Neurological and developmental manifestations of TSC included in the study were subependymal giant cell astrocytoma (SEGA), epilepsy, epileptic syndromes/infantile spasm, mental disability and autism, based on prevalences and expected costs to SUS. Direct medical costs per patient per year for each manifestation were estimated based on DATASUS ambulatory (high complexity) and hospital settings, whose databases included 2,016,188 and 9,236,360 persons, respectively. Epidemiologic literature was applied to correct misreported data and estimate average cost per patient per year for all manifestations. Sensitivity analysis was performed for the prevalence of manifestations. Costs were reported in 2010 Reals. RESULTS: The most prevalent procedure (and respective unit cost) for SEGA, epilepsy/epileptic syndromes/infantile spasm, and mental disability/autism were surgery (R$6302), hospitalization for uncontrolled seizure (R$585) and anti-epileptic drugs (R$1887), and psychiatric ambulatory treatment (R$275/R$892), respectively. The average direct medical costs per patient per year at SUS were R$7672 for SEGA, R$2,570 for epilepsy, R$1,349 for epileptic syndromes/infantile spasm, R$4668 for mental disability and R$2,276 for autism. Average cost per patient per year for all manifestations was R$19,180. This cost varied from R$13,580 to R$22,556 in sensitivity analysis. TSC neurological and developmental manifestation costs are expected to be underestimated due to lack of access and provision of health services, mainly in long-term disorders. CONCLUSIONS: TSC neurological and developmental manifestations impose significant economic burden to the Brazilian public health care system. However, the real economic burden is potentially higher as the diagnosis and treatment of the disease and its manifestations are underestimated considering restrictions of access and health service provision.